Kamath Amrita V, Chong Saeho, Chang Ming, Marathe Punit H
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Cancer Chemother Pharmacol. 2005 Feb;55(2):110-6. doi: 10.1007/s00280-004-0873-3. Epub 2004 Aug 27.
BMS-387032, a novel cyclin-dependent kinase 2 inhibitor, is currently in phase I clinical trials for anticancer therapy. The oral bioavailability of BMS-387032 has been found to be about 31% in rats. Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability in rats.
Male Sprague-Dawley rats were given single doses of BMS-387032 intraarterially (9.1 mg/kg), orally (9.1 mg/kg), or intraportally (10 mg/kg). The routes of excretion of BMS-387032 after intravenous dosing were investigated in bile-duct-cannulated rats. The rate of metabolism of BMS-387032 was investigated in liver microsomes. The permeability of BMS-387032 was evaluated using Caco-2 cells, an in vitro model of the intestinal epithelium. To determine if BMS-387032 was a P-glycoprotein substrate, brain uptake studies were conducted in P-glycoprotein knockout versus wildtype mice.
The exposure in rats after an intraportal dose was similar to that after an intraarterial dose, indicating that absorption may play a greater role than liver first-pass metabolism in the low oral bioavailability seen in rats. After an intravenous dose, the percent of dose excreted unchanged in the urine and bile over a 9-h period was 28% and 11%, respectively. In vitro studies in rat liver microsomes showed low rates of metabolism of BMS-387032. The Caco-2 cell permeability of BMS-387032 was <15 nm/s in the apical to basolateral direction, and 161 nm/s in the basolateral to apical direction, indicating that it may be a substrate for an intestinal efflux transporter. A P-glycoprotein binding assay showed that BMS-387032 might be a P-glycoprotein modulator. Brain penetration studies in mice showed brain levels of BMS-387032 about 3.5-fold higher in P-glycoprotein knockout mice than in wildtype mice, providing evidence of BMS-387032 being a P-glycoprotein substrate.
Poor absorption may be playing a greater role than extensive first-pass metabolism in the incomplete oral bioavailability of BMS-387032 seen in rats. The efflux transporter, P-glycoprotein, may be responsible for limiting absorption, as BMS-387032 appears to be a substrate of P-glycoprotein.
新型细胞周期蛋白依赖性激酶2抑制剂BMS-387032目前正处于抗癌治疗的I期临床试验阶段。已发现BMS-387032在大鼠中的口服生物利用度约为31%。对吸收和首过代谢进行了评估，以探究大鼠口服生物利用度不完全的可能原因。
给雄性Sprague-Dawley大鼠分别动脉内注射（9.1mg/kg）、口服（9.1mg/kg）或门静脉内注射（10mg/kg）单剂量的BMS-387032。在胆管插管大鼠中研究了静脉给药后BMS-387032的排泄途径。在肝微粒体中研究了BMS-387032的代谢速率。使用肠上皮细胞的体外模型Caco-2细胞评估了BMS-387032的通透性。为确定BMS-387032是否为P-糖蛋白底物，在P-糖蛋白基因敲除小鼠与野生型小鼠中进行了脑摄取研究。
门静脉给药后大鼠体内的暴露量与动脉内给药后的相似，这表明在大鼠口服生物利用度较低的情况下，吸收可能比肝脏首过代谢起更大作用。静脉给药后，9小时内尿液和胆汁中未改变排泄的剂量百分比分别为28%和11%。大鼠肝微粒体的体外研究显示BMS-387032的代谢速率较低。BMS-387032在Caco-2细胞中的通透性，从顶端到基底外侧方向<15nm/s，从基底外侧到顶端方向为161nm/s，这表明它可能是一种肠外排转运体的底物。一项P-糖蛋白结合试验表明BMS-387032可能是一种P-糖蛋白调节剂。小鼠脑渗透研究显示，P-糖蛋白基因敲除小鼠脑中BMS-387032的水平比野生型小鼠高约3.5倍，这为BMS-387032是P-糖蛋白底物提供了证据。
在大鼠中观察到的BMS-387032口服生物利用度不完全，吸收不佳可能比广泛的首过代谢起更大作用。外排转运体P-糖蛋白可能是限制吸收的原因，因为BMS-387032似乎是P-糖蛋白的底物。
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